Failure of early lymphocyte recovery identifies sepsis patients with initial lymphopenia at highest risk for late mortality

Abstract

Background Sepsis-induced lymphopenia is associated with adverse outcomes, yet static assessments at a single time point fail to capture the clinical significance of its dynamic evolution, and the effects of the trajectories of lymphopenia on prognosis are to be elucidated in sepsis. Methods This retrospective cohort study extracted data from the MIMIC-IV (v3.1) database. Adult septic patients with initial lymphopenia (<1.0 × 10⁹/L) were included. Group-Based Trajectory Modeling (GBTM) identified lymphocyte count trajectories. Kaplan-Meier analysis with log-rank test was used to visualize survival differences. Multivariable Cox and logistic regression assessed associations between trajectories and 7-day, 28-day, ICU, and in-hospital mortality. Subgroup analyses validated result consistency. Results A total of 1,640 patients were included. GBTM identified 4 distinct lymphocyte count trajectories. Kaplan-Meier analysis revealed that patients in Trajectory 4 (Persistent Low Level, N = 544, 33.2%), characterized by persistent lymphopenia, had the lowest cumulative 7-day and 28-day survival rates. After multivariable adjustment, Trajectory 4 was independently associated with an increased risk of 28-day mortality [adjusted HR = 1.76, 95% CI: 1.266–2.446, P = 0.001], ICU mortality (adjusted OR = 1.831, 95% CI: 1.196–2.832, P = 0.006), and in-hospital mortality (adjusted OR = 1.881, 95% CI: 1.298–2.767, P = 0.001) compared to Trajectory 1 (Sustained Recovery), and these associations remained robust across all predefined subgroups. In contrast, no significant association was observed between Trajectory 4 and 7-day mortality after full adjustment for confounders. Conclusion Lymphocyte count Trajectory 4 (Persistent Low Level) in initially lymphopenic sepsis patients is independently associated with late (28-day) but not early (7-day) mortality, as well as worse ICU and hospital outcomes. Failure of lymphopenia to recover by days 3–4 may signal a transition to the highest-risk state, suggesting a potential window for immunomodulatory strategies.